rs104886161

Positions:

• chrX-108601989-G-A
• chrX-108601989-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_033380.3(COL4A5):​c.2146G>A​(p.Gly716Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G716G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: COL4A5 NM_033380.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.07

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a compositionally_biased_region Pro residues (size 61) in uniprot entity CO4A5_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-108601989-G-A is Pathogenic according to our data. Variant chrX-108601989-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1077046.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.2146G>A	p.Gly716Ser	missense_variant, splice_region_variant	27/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.2146G>A	p.Gly716Ser	missense_variant, splice_region_variant	27/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.970G>A	p.Gly324Ser	missense_variant, splice_region_variant	11/20	1
COL4A5	ENST00000361603.7	c.2146G>A	p.Gly716Ser	missense_variant, splice_region_variant	27/51	2		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 917930 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 245198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Precision Medicine Center, Zhengzhou University

-

PVS1:Null variant in the gene with established LOF as a disease mechanism PM2:not found in gnomAD PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	36
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D;D;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0070	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.85
MutPred		0.98		Gain of phosphorylation at G716 (P = 0.0062);Gain of phosphorylation at G716 (P = 0.0062);.;
MVP		1.0
MPC		0.30
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: -42
DS_DL_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107845219;